Radium Ra 223 Dichloride Injection
TABLE OF CONTENTS
Radium Ra 223 dichloride, an alpha particle-emitting pharmaceutical, is a radiotherapeutic drug.
Radium Ra 223 dichloride is supplied as a clear, colorless, isotonic, and sterile solution to be administered intravenously with pH between 6 and 8.
Each milliliter of solution contains 1,000 kBq radium-223 dichloride (27 microcurie), corresponding to 0.53 ng radium-223, at the reference date. Radium is present in the solution as a free divalent cation.
Each vial contains 6 mL of solution (6,000 kBq (162 microcurie) radium-223 dichloride at the reference date). The inactive ingredients are 6.3 mg/mL sodium chloride USP (tonicity agent), 7.2 mg/mL sodium citrate USP (for pH adjustment), 0.2 mg/mL hydrochloric acid USP (for pH adjustment), and water for injection USP.
The molecular weight of radium-223 dichloride, 223RaCl2, is 293.9 g/mol.
Radium-223 has a half-life of 11.4 days. The specific activity of radium-223 is 1.9 MBq (51.4 microcurie)/ng.
The six-stage-decay of radium-223 to stable lead-207 occurs via short-lived daughters, and is accompanied predominantly by alpha emissions. There are also beta and gamma emissions with different energies and emission probabilities. The fraction of energy emitted from radium-223 and its daughters as alpha-particles is 95.3% (energy range of 5 -7.5 MeV). The fraction emitted as beta-particles is 3.6% (average energies are 0.445 MeV and 0.492 MeV), and the fraction emitted as gamma-radiation is 1.1% (energy range of 0.01 -1.27 MeV).
|2. INDICATIONS AND USAGE|
Radium Ra 223 dichloride is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.
|3. DOSAGE AND ADMINISTRATION|
3.1 Recommended Dosage
The dose regimen of radium Ra 223 dichloride is 50 kBq (1.35 microcurie) per kg body weight, given at 4 week intervals for 6 injections. Safety and efficacy beyond 6 injections with radium Ra 223 dichloride have not been studied.
The volume to be administered to a given patient should be calculated using the:
• Patient’s body weight (kg)
• Dosage level 50 kBq/kg body weight or 1.35 microcurie/kg body weight
• Radioactivity concentration of the product (1,000 kBq/mL; 27 microcurie/mL) at the reference date
• Decay correction factor to correct for physical decay of radium-223.
The total volume to be administered to a patient is calculated as follows:
Table 1: Decay Correction Factor Table
The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To determine the decay correction factor, count the number of days before or after the reference date. The Decay Correction Factor Table includes a correction to account for the 7 hour time difference between 12 noon Central European Time (CET) at the site of manufacture and 12 noon US CST, which is 7 hours earlier than CET.
Immediately before and after administration, the net patient dose of administered radium Ra 223 dichloride should be determined by measurement in an appropriate radioisotope dose calibrator that has been calibrated with a National Institute of Standards and Technology (NIST) traceable radium-223 standard (available upon request from Bayer) and corrected for decay using the date and time of calibration. The dose calibrator must be calibrated with nationally recognized standards, carried out at the time of commissioning, after any maintenance procedure that could affect the dosimetry and at intervals not to exceed one year.
Administer radium Ra 223 dichloride by slow intravenous injection over 1 minute. Flush the intravenous access line or cannula with isotonic saline before and after injection of radium Ra 223 dichloride.
3.3 Instructions for Use/Handling
Radium Ra 223 dichloride (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal radium Ra 223 dichloride are subject to the regulations and/or appropriate licenses of the competent official organization.
Radium Ra 223 dichloride should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.
The administration of radium Ra 223 dichloride is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations.
For drug handling
Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of radium Ra 223 dichloride, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diaminetetraacetic acid (EDTA) solution is recommended to remove contamination.
For patient care
Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with radium Ra 223 dichloride or patient fecal matter or urine should be washed promptly and separately from other clothing.
Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations.
The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of radium Ra 223 dichloride and the detection of contamination with standard instruments.
Instructions for preparation
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Radium Ra 223 dichloride is a ready-to-use solution and should not be diluted or mixed with any solutions. Each vial is for single use only.
The absorbed radiation doses in major organs were calculated based on clinical biodistribution data in five patients with castration-resistant prostate cancer. Calculations of absorbed radiation doses were performed using OLINDA/EXM (Organ Level INternal Dose Assessment/EXponential Modeling), a software program based on the Medical Internal Radiation Dose (MIRD) algorithm, which is widely used for established beta and gamma emitting radionuclides. For radium-223, which is primarily an alpha particle-emitter, assumptions were made for intestine, red marrow and bone/osteogenic cells to provide the best possible absorbed radiation dose calculations for radium Ra 223 dichloride, considering its observed biodistribution and specific characteristics.
The calculated absorbed radiation doses to different organs are listed in Table 2. The organs with highest absorbed radiation doses were bone (osteogenic cells), red marrow, upper large intestine wall, and lower large intestine wall. The calculated absorbed doses to other organs are lower.
Table 2: Calculated Absorbed Radiation Doses to Organs
1 LLI: lower large intestine
2 ULI: upper large intestine
Radium Ra 223 dichloride is contraindicated in pregnancy.
Radium Ra 223 dichloride can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Radium Ra 223 dichloride is not indicated for use in women. Radium Ra 223 dichloride is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
|5. WARNINGS AND PRECAUTIONS|
5.1 Bone Marrow Suppression
In the randomized trial, 2% of patients on the radium Ra 223 dichloride arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with radium Ra 223 dichloride, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the radium Ra 223 dichloride arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression.
In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of radium Ra 223 dichloride-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with radium Ra 223 dichloride and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with radium Ra 223 dichloride. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of radium Ra 223 dichloride, neutrophil and platelet count nadirs occurred 2 to 3 weeks after radium Ra 223 dichloride administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)].
Hematologic evaluation of patients must be performed at baseline and prior to every dose of radium Ra 223 dichloride. Before the first administration of radium Ra 223 dichloride, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of radium Ra 223 dichloride, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of radium Ra 223 dichloride, despite receiving supportive care, further treatment with radium Ra 223 dichloride should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue radium Ra 223 dichloride in patients who experience life-threatening complications despite supportive care for bone marrow failure.
The safety and efficacy of concomitant chemotherapy with radium Ra 223 dichloride have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, radium Ra 223 dichloride should be discontinued.
|6. ADVERSE REACTIONS|
The following serious adverse reactions are discussed in greater detail in another section of the label:
• Bone Marrow Suppression [see Warnings and Precautions (5.1)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) of radium Ra 223 dichloride and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the radium Ra 223 dichloride and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for radium Ra 223 dichloride and 18 weeks (5 cycles) for placebo.
The most common adverse reactions (≥ 10%) in patients receiving radium Ra 223 dichloride were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of radium Ra 223 dichloride-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in radium Ra 223 dichloride-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).
Treatment discontinuations due to adverse events occurred in 17% of patients who received radium Ra 223 dichloride and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for radium Ra 223 dichloride were anemia (2%) and thrombocytopenia (2%).
Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for radium Ra 223 dichloride exceeds the incidence for placebo.
Table 3: Adverse Reactions in the Randomized Trial
Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for radium Ra 223 dichloride exceeds the incidence for placebo.
Table 4: Hematologic Laboratory Abnormalities
Laboratory values were obtained at baseline and prior to each 4-week cycle.
As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on radium Ra 223 dichloride and in 2% of patients on placebo. Among patients who received radium Ra 223 dichloride, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.
Dehydration occurred in 3% of patients on radium Ra 223 dichloride and 1% of patients on placebo. Radium Ra 223 dichloride increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.
Injection Site Reactions
Erythema, pain, and edema at the injection site were reported in 1% of patients on radium Ra 223 dichloride.
Secondary Malignant Neoplasms
Radium Ra 223 dichloride contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, radium Ra 223 dichloride may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the radium Ra 223 dichloride arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.
Subsequent Treatment with Cytotoxic Chemotherapy
In the randomized clinical trial, 16% patients in the radium Ra 223 dichloride group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with radium Ra 223 dichloride will tolerate subsequent cytotoxic chemotherapy.
|7. DRUG INTERACTIONS|
No formal clinical drug interaction studies have been performed.
Subgroup analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did not affect the safety and efficacy of radium Ra 223 dichloride in the randomized clinical trial.
|8. USE IN SPECIFIC POPULATIONS|
8.1 Usage in Pregnancy
Pregnancy Category X
[see Contraindications (4)]
Radium Ra 223 dichloride can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of radium Ra 223 dichloride in pregnancy and radium Ra 223 dichloride is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Radium Ra 223 dichloride is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with radium Ra 223 dichloride.
8.2 Nursing Mothers
Radium Ra 223 dichloride is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from radium Ra 223 dichloride, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.
8.3 Pediatric Use
The safety and efficacy of radium Ra 223 dichloride in pediatric patients have not been established.
In single-and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, fibroosseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 – 80 kBq (0.541 -2.16 microcurie) per kg body weight.
8.4 Geriatric Use
Of the 600 patients treated with radium Ra 223 dichloride in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.5 Patients with Hepatic Impairment
No dedicated hepatic impairment trial for radium Ra 223 dichloride has been conducted. Since radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.
8.6 Patients with Renal Impairment
No dedicated renal impairment trial for radium Ra 223 dichloride has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/min) due to limited data available (n = 2).
8.7 Males of Reproductive Potential
Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with radium Ra 223 dichloride.
There are no data on the effects of radium Ra 223 dichloride on human fertility. There is a potential risk that radiation by radium Ra 223 dichloride could impair human fertility.
There have been no reports of inadvertent overdosing of radium Ra 223 dichloride during clinical studies.
There is no specific antidote. In the event of an inadvertent overdose of radium Ra 223 dichloride, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1
Single radium Ra 223 dichloride doses up to 250 kBq (6.76 microcurie) per kg body weight were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed.
|10. MECHANISM OF ACTION|
The active moiety of radium Ra 223 dichloride is the alpha particle-emitting isotope radium-223 (as radium Ra 223 dichloride), which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases (see Table 2). The high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The alpha particle range from radium-223 dichloride is less than 100 micrometers (less than 10 cell diameters) which limits damage to the surrounding normal tissue.
Compared with placebo, there was a significant difference in favor of radium Ra 223 dichloride for all five serum biomarkers for bone turnover studied in a phase 2 randomized study (bone formation markers: bone alkaline phosphatase [ALP], total ALP and procollagen I N propeptide [PINP], bone resorption markers: C-terminal crosslinking telopeptide of type I collagen [S-CTX-I] and type I collagen crosslinked C-telopeptide [ICTP]).
The pharmacokinetics of radium-223 dichloride in blood was linear in terms of dose proportionality and time independence in the dose range investigated (46 to 250 kBq [1.24 to 6.76 microcurie] per kg body weight).
After intravenous injection, radium-223 is rapidly cleared from the blood and is distributed primarily into bone or is excreted into intestine. Fifteen minutes post-injection, about 20% of the injected radioactivity remained in blood. At 4 hours, about 4% of the injected radioactivity remained in blood, decreasing to less than 1% at 24 hours after the injection. At 10 minutes post-injection, radioactivity was observed in bone and in intestine. At 4 hours post-injection, the percentage of the radioactive dose present in bone and intestine was approximately 61% and 49%, respectively. No significant uptake was seen in other organs such as heart, liver, kidneys, urinary bladder, and spleen at 4 hours post-injection [see Dosage and Administration (3.3)].
Radium-223 is an isotope that decays and is not metabolized.
The whole body measurements indicated that approximately 63% of the administered radioactivity was excreted from the body within 7 days after injection (after correcting for decay). Fecal excretion is the major route of elimination from the body. At 48 hours after injection, the cumulative fecal excretion was 13% (range 0 -34%), and the cumulative urine excretion was 2% (range 1 -5%). There was no evidence of hepato-biliary excretion based on imaging data.
The rate of elimination of radium-223 dichloride from the gastrointestinal tract is influenced by the high variability in intestinal transit rates across the population. Patients with a slower intestinal transit rate could potentially receive a higher intestinal radiation exposure. It is not known whether this will result in increased gastrointestinal toxicity.
Safety and effectiveness of radium Ra 223 dichloride have not been established in children and adolescents below 18 years of age.
Patients with hepatic impairment
No dedicated pharmacokinetic study in patients with hepatic impairment has been conducted. However, since radium-223 is not metabolized and there is no evidence of hepato-biliary excretion based on imaging data, hepatic impairment is not expected to affect the pharmacokinetics of radium-223 dichloride.
Patients with renal impairment
No dedicated pharmacokinetic study in patients with renal impairment has been conducted. However, since excretion in urine is minimal and the major route of elimination is via the feces, renal impairment is not expected to affect the pharmacokinetics of radium-223 dichloride.
|13. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand name: XOFIGO, by Bayer Pharms.
b) Generic drugs: None.
2) How Supplied:
Xofigo (radium Ra 223 dichloride injection) is supplied in single-use vials containing 6 mL of solution at a concentration of 1,000 kBq/mL (27 microcurie/mL) with a total radioactivity of 6,000 kBq/vial (162 microcurie/vial) at the reference date (NDC 50419-208-01).
3) Storage and Handling:
Store at room temperature, below 40° C (104° F). Store Xofigo in the original container or equivalent radiation shielding.
This preparation is approved for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.
Follow procedures for proper handling and disposal of radioactive pharmaceuticals [see Dosage and Administration (3.3)].